Predicting the clinical trajectory of feeding and swallowing abilities in CHARGE syndrome

**Background:** CHARGE syndrome (CS) is a rare autosomal dominant disorder caused by CHD7 variants, with an incidence of 0.1–1.2/10,000 live births. Feeding problems and swallowing dysfunction affect over 90% of individuals, yet longitudinal data on skill progression by age have been lacking. This study aimed to evaluate the evolution of feeding and swallowing abilities with age in a molecularly confirmed CS cohort.

**Methods:** The authors retrospectively analysed clinical records of 16 patients (8 male; age range 4–21 years; mean 11 years; SD 6 years; median 10 years) with molecularly confirmed CS and feeding difficulties, followed at the Rare Disease Unit, Paediatrics Department, Fondazione Policlinico Agostino Gemelli-IRCCS, Rome, between 2011 and 2021. All patients carried de novo CHD7 variants: 9 truncating (5 nonsense, 4 frameshift), 2 missense, and 5 splice site changes. Comprehensive feeding and swallowing assessments were conducted according to the WHO International Classification of Functioning, Disability and Health (ICF) framework, including oral-motor evaluation, observation of oral-facial structures, assessment of developmental skills, behavioural factors, and food texture tolerance. Instrumental assessments (Videofluoroscopic Swallow Study and radionuclide salivagram) were used when available. Descriptive statistics were performed.

**Key Results:** All 16 newborns (100%) had weak suckling at birth, and 50% demonstrated poor coordination between breathing and swallowing. Nine newborns (56%) required total enteral nutrition (TEN) via nasogastric tube. By 6 months, 31% (5/16) remained tube-dependent, and 19% (3/16) had severe aspiration risk on salivagram. At 12 months, 25% (4/16) still required TEN, and none had started eating soft solid food. At 24 months, no child had achieved a mature chewing pattern, and 25% (4/16) still needed TEN via G-tube. After age 2 years, 14/16 patients showed light but steady improvement. Among oral feeders, the median age for starting foods requiring chewing and for taste discrimination was 6 years (maximum 12 years). A mature chewing pattern with safe swallowing for all textures was achieved by 6/14 oral feeders (43% of the whole cohort, 7/16) at a median age of 8.5 years. Adequate oral-sensory processing was reached at a median age of 5.5 years. By school age, 13% (3/16) remained tube-dependent, all with severe multiple cranial nerve involvement; two also required tracheostomy. The four children with persistent worse outcomes (long-term enteral feeding with or without tracheal cannula) all had truncating mutations, while those with splice site changes had relatively milder phenotypes that improved with age.

**Clinical Implications:** This first longitudinal study of feeding skills in CHARGE syndrome provides age-specific benchmarks for clinicians. Although feeding difficulties are nearly universal in CS, most children show gradual improvement over time, with tube feeding dependence decreasing from 60% at birth to 13% at school age. Early speech language therapy intervention appears critical for promoting oral feeding success and weaning from enteral nutrition. The data suggest that children with severe cranial nerve dysfunction and laryngeal/tracheal/oesophageal malformations at birth have the poorest long-term outcomes. The study is limited by its small sample size (n=16) and retrospective design, requiring validation by independent studies.